CLL Treatment: 100% Response with VenR Retreatment

Patients with relapsed or treatment-resistant chronic lymphocytic leukemia (CLL) have reason for optimism: a combination of venetoclax and rituximab (VenR) has demonstrated a 100% response rate and prolonged progression-free survival (PFS) in a recent study. This offers a powerful second chance for those whose disease has returned.

A Second Chance at Remission: VenR Shows Remarkable Efficacy

A new analysis reveals sustained benefits from retreatment with the VenR combination, offering hope for durable responses in CLL.

• The median PFS from the first VenR treatment was an impressive 9.5 years.
• Retreatment with VenR yielded a median PFS of 4.9 years.
• All nine patients in the study responded to retreatment, with most achieving a partial or complete response.
• Long-term analysis showed four patients remained progression-free for over a year after restarting treatment.

The findings, published in HemaSphere, suggest that patients can safely and effectively be retreated with VenR even after their disease progresses following initial therapy.

Study Details and Patient Characteristics

The analysis included nine patients—four men and five women—participating in the phase 1b M13-365 study (NCT01682616). Participants, enrolled between August 6, 2012, and May 28, 2014, ranged in age from 58 to 79 years and had received between one and four prior therapies.

Before retreatment, the median lymphocyte count was 22.5 x 10⁹/L, and the maximum lymph node size was 34.8 mm. Genomic testing revealed that one patient each had a del(17p) deletion or a TP53 mutation, while two patients exhibited IGHV-mutated disease.

Treatment Protocol and Responses

Patients initially responded well to treatment, with six achieving a complete response (CR), two a CR with incomplete recovery (CRi), and one a partial response (PR). Upon retreatment, three patients achieved a CR, and six experienced a PR.

The retreatment protocol involved a 5-week ramp-up to a daily oral dose of 400 mg venetoclax, followed by 375 mg/m² of rituximab starting on day 1 of week 6, with monthly doses of 500 mg/m² rituximab for five months.

These results are promising because the median time off treatment was longer compared with other studies, and they support the authors’ theory that fixed-duration treatment shows promise at lessening patient risk of developing future treatment resistance.

Durable Responses and Genomic Factors

Progressive disease after initial therapy was defined as two consecutive peripheral blood measures with minimal residual disease (MRD) values greater than 10^-4 or a single measure greater than 10^-3. Disease status was confirmed via CT scan, MRI, and bone marrow biopsy before retreatment.

Prior to initial therapy, seven patients had undetectable MRD (uMRD) in their bone marrow alone (one patient) or both bone marrow and peripheral blood (six patients). Before retreatment, only one patient had uMRD in both bone marrow and peripheral blood, while others showed varying levels of MRD positivity.

Patients were off treatment for a median of 38.4 months (range, 17.3-68.7) before disease progression and initiating retreatment, with a median time of 4.9 months between progression confirmation and retreatment. As of December 31, 2023, four of the nine patients remain progression-free for over a year after restarting treatment.

A subanalysis of six patients who had acquired BCL2 mutations after previous venetoclax-based therapies showed no evidence of the mutation in four patients tested before retreatment and in the remaining two tested after retreatment. All patients tested for del(17p) or TP53 mutations before retreatment were negative for del(17p), but one patient was positive for TP53.

Implications for Treatment Strategies

“As the protocol had the distinctive option, but not requirement, to discontinue treatment if in a deep response, it permitted the within‐trial comparison that demonstrated that PFS off therapy in deep response was like that of patients who remained on continuous therapy after achieving deep response,” the study authors wrote. “The M13‐365 study provided the first prospective evidence that CLL/SLL response can be maintained off treatment if patients achieved a deep response to initial VenR.”

These findings are encouraging, as the median time off treatment observed in this study was longer than in other studies^2,3, supporting the idea that fixed-duration treatment may reduce the risk of developing future treatment resistance^4,5.

1. Brander DM, Roberts AW, Kipps TJ, et al. Retreatment with venetoclax and
   rituximab following disease progression while off therapy in patients with
   chronic lymphocytic leukemia. Hemasphere. 2025;9(12):e70284.
   doi:10.1002/hem3.70284
2. Kater AP, Harrup R, Kipps TJ, et al. The MURANO study: final analysis and
   retreatment/crossover substudy results of VenR for patients with
   relapsed/refractory CLL. Blood. 2025;145(23):2733‐2745.
   doi:10.1182/blood.2024025525
3. Thompson MC, Harrup RA, Coombs CC, et al. Venetoclax retreatment of
   patients with chronic lymphocytic leukemia after a previous venetoclax‐based
   regimen. Blood Adv. 2022;6(15):4553‐4557.
   doi:10.1182/bloodadvances.2022007812
4. Popovic R, Dunbar F, Lu C, et al. Identification of recurrent genomic
   alterations in the apoptotic machinery in chronic lymphocytic leukemia
   patients treated with venetoclax monotherapy. Am J Hematol.
   2022;97(2):e47‐e51. doi:10.1002/ajh.26411
5. Blombery P, Thompson ER, Nguyen T, et al. Multiple BCL2 mutations
   cooccurring with Gly101Val emerge in chronic lymphocytic leukemia
   progression on venetoclax. Blood. 2020;135(10):773‐777.
   doi:10.1182/blood.2019004205